Antibodies are capable of preventing lentivirus infections. However, the mechanisms by which they achieve protection in vivo are largely unknown. In the presence of natural killer (NK) effector cells, antibody inhibits viral yield from lymphocytes infected with clinical strains of HIV-1. This antibody-dependent cell-mediated virus inhibition (ADCVI) reduces HIV-1 yield by mediating lysis of target cells expressing HIV-1 glycoproteins. Moreover, ADCVI inhibits virus by augmenting beta-chemokine release from NK cells, a novel and exciting finding indicating that antibody can render lymphocytes refractory to infection without binding to and neutralizing cell- free virus. In contrast to neutralizing antibody, ADCVI antibody is detectable very early during acute HIV infection while viremia levels decline, and the magnitude of the ADCVI antibody response is inversely associated with HIV-1 RNA level. ADCVI may thus be a critical factor in the early control of viremia. In this project, key features of ADCVI antibody and effector cell functions will be addressed with the long-term goal of developing and testing ADCVI-based vaccine, immunotherapy and immunoprophylaxis strategies. The following hypotheses will be tested: a) An antibody response to specific epitopes contributes to limiting viremia during acute HIV infection; b) ADCVI inhibits a broad range of HIV-1 strains and; c) NK cells, macrophages and gamma-delta-T cells all mediate ADCVI, and ADCVI is due in part to protection of uninfected cells by beta-chemokines. The specific aims are: 1) Identify epitopes that elicit the ADCVI antibody response during acute HIV infection by using monoclonal antibody (mAb) F(ab)'2 fragment competition and a novel phage display library approach; 2) Using antibodies from HIV-infected patients at different stages of infection, measure ADCVI against a panel of diverse HIV-1 strains and measure the relationship between antibody affinity and ADCVI antibody function and; 3) Determine if macrophages and gamma-delta-T cells-in addition to NK cells- mediate ADCVI, quantify the contribution of beta-chemokines to the anti-viral effect of ADCVI, and evaluate the impact of cytokine activation on ADCVI effector cell function. This project may provide crucial insights for guiding the development of vaccines, immunoprophylaxis and immunotherapy.